Granik calls filmmaking "an organic, incremental process". Her first short, Snake Feed, was accepted into Sundance Film Festival's labs for screenwriting and directing, and eventually this short grew into her first feature-length film, Down to the Bone in 2004.[2] This film tells the story of an upstate New York mother who goes to rehab to kick her cocaine addiction and ends up falling in love with a nurse and, with his help, descending back into her old drug habits.[3] This film was based on an original screenplay written by Granik and her creative partner, Anne Rosellini. The main character, played by Vera Farmiga, was inspired by a woman that Granik met while attending film school in New York.[2]

The film was shot on location in the Ozark territory of Missouri. Granik cast many of the supporting roles with first-time actors from the surrounding area[5] and all of the homes on screen were established Ozark homes—no sets were built for this film.[4] For the look of the film, Granik kept most of the established aesthetics of the homes in which they were shooting and many of the few mementos that were added to the homes were contributed by Ozark people in the community.[3]

Granik is set to produce and direct an HBO television pilot called American High Life, although the pilot had not been greenlit as of May 2012. The show is a family drama that "follows a young career woman to her economically depressed small home town in the midwest". Granik is also developing a film adaption of Rule of the Bone, a 1995 novel by Russell Banks.[6]

Interviewed by Jeremiah Kipp, Granik gave an overview of the challenges involved in doing a film about addiction:

The traditional storyline in an American film is usually in the form of a V shape. I am oversimplifying, but we see someone tumbling down, they hit bottom, and then they rise up again and find redemption. Anyone who personally, tangentially or culturally knows anything about addiction is aware that it resembles an EKG. Up and down, up and down. Very few people ever get clean on the first or second attempt. For many people, it’s something they have to try over and over again. You get knocked down and ask all the ethical questions like how many chances do you give a person? When is the last chance? How many chances do they get? Can you imagine how difficult it is to fit that in a feature-length film? But those are the questions that are worth asking... The reason why boils down to the word “dark”. It is the scariest four-letter word in American storytelling and in this culture. Our film had a strong reception in Europe and achieved distribution, but that was not the case here. We received so many responses like, “We love the film, but we cannot do anything with it or we’ll lose our shirts. We’re sorry.” The intervention comes from people like Laemmle/Zeller Films. Every couple of years, some mavericks take on this challenge of distributing so-called un-distributable films. They take those films on a small run and allow them to see the light of day. Those efforts are what give a film like Down to the Bone a chance to have a life of some kind.[7]